Immunotherapeutic processes are playing an increasing role in the treatment of diseases, particularly cancer and infections, that hitherto could only be controlled with difficulty or inadequately. In this connection, use is preferably made of antibodies by way of immunostimulating agents; cf. Glennie and Johnson (2000) Immunology Today 21(8): 403-410. The efficacy of immunostimulating antibodies of such a type is based, in particular, on the possibility of the specific binding of defined antigens. However, a great problem in connection with the combating of diseases such as cancer and infections by means of immunostimulating antibodies hitherto has been constituted by the severe side-effects caused by the application of antibodies of such a type, in which connection severe malaise, vomiting, allergic reactions, hypotension, tachycardia, high fever and even fatal circulatory failure or organ failure have been observed in particular, mostly by reason of a SIRS (systemic inflammatory response syndrome).
These intense side-effects of immunostimulating antibodies correlate in most cases with a non-specific release of cytokine, caused by the antibodies, which is responsible for a large proportion of the stated clinical side-effects. The extent of the release of cytokine, which is dependent on the quantity applied and on the velocity of application of the immunostimulating antibody, limits the compatible dose of the respective immunostimulating antibody in clinical use.
Glucocorticoids have long been known as highly effective anti-inflammatory and immunosuppressant active substances. One mechanism in the context of the immunosuppressant action of glucocorticoids is the attenuating action thereof on the transcription of cytokines; cf., for example, Blotta et al. (1997) J. Immunol. 158: 5589 to 5595; Ballow and Nelson (1997) JAMA 278 (22), Chapter 24: 2008 to 2017. In recent years, further advances have been made with regard to the investigation of the immunosuppressant action of glucocorticoids, particularly in connection with the development of T-cells and the function thereof; presented synoptically, for example, in Ashwell and Vacchio (2000) Annu. Rev. Immunol. 18: 309 to 345. In the development of effective immunosuppressant therapies, particularly in connection with the prevention of (acute) transplant rejections, use is preferably made of glucocorticoids in combination with further immunosuppressant agents. For instance, Herbelin et al. (Transplantation (2000) 68 (5): 616 to 622) report an improvement in acute immunosuppression therapy with the anti-CD3 antibody OKT3 with prior administration of glucocorticoids by reason of the reduction, caused by said glucocorticoids, of the production of TNF-α, IL-2 and IFN-γ. However, in the state of the art an administration of glucocorticoids in connection with the stimulation of the immune system of a patient by antibody therapies, for example with trifunctional antibodies (trAB), is totally unknown. In particular, glucocorticoids have been employed hitherto when an immunosuppression was the therapeutic aim.
The object underlying the present invention is therefore to provide a new system for the most extensive possible alleviation of the side-effects of antibodies acting in immunostimulatory manner.
This object is achieved by the embodiments of the present invention that are characterised in the claims.